RACK1 Regulates VEGF/Flt1-mediated Cell Migration via Activation of a PI3K/Akt Pathway

Abstract

Vascular endothelial growth factor (VEGF) is vital to physiological as well as pathological angiogenesis, and regulates a variety of cellular functions, largely by activating its 2 receptors, fms-like tyrosine kinase (Flt1) and kinase domain receptor (KDR). KDR plays a critical role in the proliferation of endothelial cells by controlling VEGF-induced phospholipase C␥-protein kinase C (PLC␥-PKC) signaling. The function of Flt1, however, remains to be clarified. Recent evidence has indicated that Flt1 regulates the VEGF-triggered migration of endothelial cells and macrophages. Here, we show that RACK1, a ubiquitously expressed scaffolding protein, functions as an important regulator of this process. We found that RACK1 (receptor for activated protein kinase C 1) binds to Flt1 in vitro. When the endogenous expression of RACK1 was attenuated by RNA interference, the VEGF-driven migration was remarkably suppressed whereas the proliferation was unaffected in a stable Flt1-expressing cell line, AG1-G1-Flt1. Further, we demonstrated that the VEGF/Flt-mediated migration of AG1-G1-Flt1 cells occurred mainly via the activation of the PI3 kinase (PI3K)/ Akt and Rac1 pathways, and that RACK1 plays a crucial regulatory role in promoting PI3K/Akt-Rac1 activation.

The Association of Receptor of Activated Protein Kinase C 1(RACK1) with Infectious Bursal Disease Virus Viral Protein VP5 and Voltage-dependent Anion Channel 2 (VDAC2) Inhibits Apoptosis and Enhances Viral Replication

“…Currently it is still not clear how these proteins interact and act during IBDV infection. On the other hand, IBDV could activate the PI3K/Akt signaling pathway via interaction of VP5 protein with the p85 ␣ subunit of PI3K (24), whereas RACK1 could promote the activation of the PI3K/Akt/Rac1 pathway (61). RACK1 also suppressed IBDV-induced apoptosis in this study.…”

Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma

“…In addition to phosphorylation, eIF4E is also regulated at the level of availability controlled by AKT/mTOR/4E-BP pathway (43), which plays a pivotal role in pathogenesis of HCC (57). Though RACK1 has been reported to be involved in the regulation of ERK and AKT activation (58)(59)(60), introduction of RACK1 in HCC exhibited little effect on ERK/MNK and AKT/4E-BP phosphorylation (Supplemental Figure 9 and our unpublished observations). Our results suggest that aberrant expression of RACK1 in HCC contributes to vigorous protein synthesis through functioning on ribosome, and the underlying mechanism that regulates the binding of RACK1 to ribosome needs further investigation.…”

The Ins and Outs of Small GTPase Rac1 in the Vasculature

“…Interestingly, Rac1 activation reduces VEGFinduced vascular leakage (Hoang et al, 2011), yet Rac1 is essential for VEGF-induced migration (Wang et al, 2011a). Again, local activation of Rac1 very probably determines these different processes.…”